Cyclosporin is a high molecular peptide compound consisting of 11 amino acids which achieves its potent immunosuppressive activity by inhibiting the growth and differentiation of T cells. There are many cyclosporins such as cyclosporin A, B, C, D, G, etc. depending on the structure of constituent amino acids, but cyclosporin A is preferable used in the clinical field since its pharmacological activity and clinical indication and effectiveness are well established in the art. Cyclosporin is used clinically to prevent allograft rejection after transplantation of tissue or organ such as kidney, liver, heart, bone marrow, pancreas, skin, cornea, etc. And it has been applied to treat autoimmune diseases, especially inflammation disease such as rheumarthritis.
Cyclosporin has a unique structure, which is a cyclic oligopeptide consisting of 11 amino acids. The seven amino acids of cyclosporin are N-methylated. The four remaining protonated nitrogen atoms can form intermolecular hydrogen bonds with carbonyl groups, which contribute substantially to the rigidity, of the cyclosporin skeleton. Therefore, it has a remarkably hydrophobic property, and is relatively insoluble in water (for cyclosporin A. 0.04 mg/ml at 25.degree. C.). Due to such a low water-solubility of cyclosporin, the bioavailability of cyclosporin A is known to be 30% or less. It was reported that the absorption of such an insoluble compound is greatly influenced by bile juice secretions, the amount of fat in food, etc. In the case of cyclosporin A, it has been reported that differences in absorption between individuals are as great as about 5.about.50%.
10.about.27% of cyclosporin A absorbed were eliminated by first-pass effect in liver, the half life for distribution of cyclosporin A is 0.7.about.1.7 h, and the half life for elimination of cyclosporin A is 6.2.about.23.9 h. The said pharmacological parameters show a large individual difference according to bile juice secretion, the condition of patient transplanted and the kind of transplantation organ.
Even though cyclosporin has almost no bone marrow toxicity unlike other immunosuppressants, it has a very narrow therapeutic range. Nephrotoxicity is the major adverse effect of cyclosporin. Cyclosporin shows adverse effects such as decreasing of glomerular filtration rate, increasing of reabsorption of proximal tubules, etc., dose-dependently. It has been reported that the appearance of an irreversible deterioration of nephron and the inducement of serious nephrotoxicity is a chronic toxicity of cyclosporin multiple dosing.
Therefore, such problems as low bioavailability due to poor aqueous solubility of cvclosporin, individual difference of cyclosporin absorption, narrow therapeutic range, adverse effects showed dose-dependently, etc., must be addressed. And recently, it has come to light that the prevention of adverse effects through a constant maintenance of blood concentration of cyclosporin within the therapeutic range is a difficult but important objective.
In various methods for improvement of nephrotoxicity of cyclosporin, using of prostaglandin derivatives that are antagonists for calcium was tried but it did not show good effect. The risk of the high fluctuation index for rejection and for nephrotoxicity might be mitigated by frequent administration of small doses, thereby maintaining blood concentration of cyclosporin within the therapeutic range. But the administration more than thrice daily is not preferable because cyclosporin usually should be administered for a long period and, in this case, because it is difficult that patient compliance would be high. Therefore, the development of a once a day dosage form of cyclosporin is preferable and expected.
Dosage form development studies of cyclosporin having the said characteristics had been mainly concentrated on the means that are used to solubilize cyclosporin.
The soft gelatin capsule that is commercialized by Sandoz Pharmaceuticals since 1990 can form a crude emulsion in the gastric-instetinal (GI) tract after oral administration. Even though it could produce the great convenience for administration method, it still has the problem that blood concentration of cyclosporin must be monitored frequently. It was because cyclosporin absorption from the said pharmaceutical preparation showed not only large individual difference but also high variability in the same patient depending on food, bile secretion, GI tract function, etc.
Recently, to solve the said problem, a new cyclosporin-preparation using microemulsion system has been developed by Novartis (Sandimmun Neoral). This pharmaceutical preparation shows that cyclosporin bioavailability is almost not affected by food, bile secretion, etc. as well as increasing of its bioavailability. Therefore, frequent monitoring of the trough level of patient is not needed, and hence is a remarkable improvement of pharmaceutical art.
U.S. Pat. No. 4.146,499 disclosed the method using w/o microemulsion using ethanol as a hydrophilic cosurfactant. And U.S. Pat. No. 5.342.625 disclosed the method using non-ethanol component as a hydrophilic cosurfactant to improve the disadvantage of using ethanol.
However, the said cyclosporin microemulsion compositions still have a problem of adverse effects induced by the peak level of blood concentration of cyclosporin. Therefore, a standard dose is administered to all patients initially, and then the blood concentration of cyclosporin must be monitored continuously on each patient. Inconveniently, dose of cyclosporin must be controlled referring to monitoring result, so that allograft rejection and nephrotoxicity would be minimized.
The objective of present invention is the produce of a controlled release preparation that can release cyclosporin for a long time in GI tract after oral administration, while solving the problems of cyclosporin preparations of prior arts.